Copper Iodide Mediated Cyanation of Arylboronic Acids and Aryl Iodides with Ethyl (Ethoxymethylene)cyanoacetate as Cyanating Agent

Article abstract of DOI:10.1055/s-0035-1562112

An efficient copper iodide mediated cyanation of arylboronic acids and aryl iodides with ethyl (ethoxymethylene)cyanoacetate as cyanating agent has been developed. The reaction involves a C(sp²)-CN bond cleavage and tolerates a wide range of functional groups, affording the corresponding aryl nitriles in moderate to excellent yields.

Full text of DOI:10.1055/s-0035-1562112

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
C. Qi et al.
Letter
Synlett
Copper Iodide Mediated Cyanation of Arylboronic Acids and Aryl
Iodides with Ethyl (Ethoxymethylene)cyanoacetate as Cyanating
Agent
Chaorong Qi*
Xiaohan Hu
Haitao He
CuI (1 equiv)
TBHP (2 equiv)
EtO2C
Ar CN
Ar
X
+
OEt
DMF, 130 °C, 24 h, air
CN
31 examples
up to 91% yield
C(sp2)
CN
X = I, B(OH)2
School of Chemistry and Chemical Engineering, State Key Lab
of Luminescent Materials and Devices, South China University
of Technology, Guangzhou 510640, P. R. of China
crqi@scut.edu.cn
Received: 20.02.2016
Accepted after revision: 01.04.2016
Published online: 04.05.2016
cyanides as cyano-group sources frequently employed by
conventional synthetic methods.3 Different organic com-
pounds, such as acetonitrile,4 acetone cyanohydrins,5 malo-
nonitrile,6 benzyl cyanide,7 and 2,2′-azobisisobutyronitrile
(AIBN),8 were successfully utilized as efficient cyanating
agent for the transition-metal-catalyzed or -mediated cy-
anantion of various substrates (Scheme 1, a). Although
great progress has been made, the development of novel,
nontoxic, and easily available cyanating agents for the cya-
nation is still highly desirable. Moreover, in most of the cas-
es mentioned above, the cyano group transfers from C(sp3)
to C(sp2). In sharp contrast, cyanation reaction involving cy-
ano-group migration from C(sp2) to C(sp2) has less been ex-
plored.
DOI: 10.1055/s-0035-1562112; Art ID: st-2016-w0122-l
Abstract An efficient copper iodide mediated cyanation of arylboron-
ic acids and aryl iodides with ethyl (ethoxymethylene)cyanoacetate as
cyanating agent has been developed. The reaction involves a C(sp2)–CN
bond cleavage and tolerates a wide range of functional groups, afford-
ing the corresponding aryl nitriles in moderate to excellent yields.
Key words copper, nitriles, transition metals, cleavage, arenes
The transition-metal-catalyzed or -mediated C–CN
bond activation and cleavage has emerged as an attractive
research topic in recent years, not only because C–CN bonds
are widely present in many functional molecules but also it
can provide novel strategies for the synthesis of a variety of
structurally diverse compounds through a series of new re-
actions, including a) decyanative cross-coupling reactions,
b) carbocyanation reactions with unsaturated hydroncar-
bons, and c) cyanation reactions (Figure 1).1
a) previous works
Pd or Cu
+
Ar
X
RCN
Ar CN
C(sp3)
OH
CN
X = H, I, Br, B(OH)2
RCN = MeCN,
,
CN
PhCH2CN
NC
,
,
AIBN
CN
(a) decyanative
cross-coupling
b) this work
C
CuI
EtO2C
+
Ar CN
Ar
X
OEt
(b) carbocyanation
C(sp2)
CN
CN
C
CN
C
CN
X = I, B(OH)2
Scheme 1 Synthesis of aryl nitriles through C–CN bond cleavage
(c) cyanation
CN
Figure 1 The application of C–CN bond cleavage in organic synthesis
Ethyl (ethoxymethylene)cyanoacetate is a versatile syn-
thetic building block,9 but its application to cyanation reac-
tion as a nonmetallic cyano-group source has never been
explored. Recently, we found that ethyl (ethoxymethy-
lene)cyanoacetate could react with α-hydroxy ketones to
furnish 2,2,4-trisubstituted 3(2H)-furanones in good yields
in the presence of copper iodide as the catalyst.10 We envi-
In particular, due to the importance of nitriles in natural
products, dyes, pharmaceuticals, and herbicides,2 cyanation
reactions via C–CN bond cleavage are of greatly synthetic
interest, as it allows to establish many elegant alternative
routes to aryl nitriles, while avoiding the use of toxic metal
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
C. Qi et al.
Letter
Synlett
sioned that ethyl (ethoxymethylene)cyanoacetate might
serve as an efficient cyanating agent for the synthesis of
aryl nitriles. Herein, we wish to report our investigation on
the cyanation of arylboronic acids and aryl iodides with
ethyl (ethoxymethylene)cyanoacetate in detail (Scheme 1, b).
Initially, we chose 4-biphenylboronic acid (1a) as the
model substrate for the optimization of the reaction condi-
tions, and the results are summarized in Table 1. When the
reaction was performed in the presence of 20 mol% of CuI
as catalyst, two equivalents of TBHP as oxidant in DMF at
100 °C under air for 24 hours, the desired product 3a was
obtained in 29% yield (Table 1, entry 1). To our delight, the
yield of 3a was increased to 82% when we used one equiva-
lent of CuI and increased the reaction temperature to
130 °C (Table 1, entry 2). Control experiments showed that
the reaction could not occur in the absence of CuI (Table 1,
entry 3). Moreover, only low yield or trace amount of 3a
was observed when the reaction was conducted without
TBHP or under a nitrogen atmosphere, indicating that both
TBHP and air are necessary for the reaction (Table 1, entries
4 and 5).
Considering that DMF have previously been employed
as the CN source,11 we performed a control experiment in
the absence of 2a. The result showed that only trace
amount of 3a was detected in this case (Table 1, entry 6),
confirming that 2a indeed act as a source of cyano group in
this transformation. Further screening of different copper
salts revealed that only CuI was effective for the reaction,
and other copper salts such as CuBr, CuCl, CuSO4, or
Cu(OAc)2 failed to give the desired product (Table 1, entries
7–10). We also investigated the influence of different sol-
vents on the reaction. DMF was found to be the best media
for the reaction while the use of dimethyl sulfoxide (DMSO)
or dimethylacetamide (DMA) as solvent resulted in a dra-
matic decrease in the yield (entries 11 and 12). The oxidant
also has an important influence on the reaction. For exam-
ple, when TBHP was replaced by benzoquinone (BQ) or di-
tert-butylperoxide (DTBP), only a low yield of 3a was ob-
tained (Table 1, entries 13 and 14). The use of molecular ox-
ygen (1 atm) as the sole oxidant afforded 3a only in 10%
yield (Table 1, entry 15).
The scope of the copper iodide promoted cyanation re-
action was subsequently investigated with various arylbo-
ronic acids (Table 2).12 To our delight, both electron-defi-
cient and electron-rich arylboronic acids underwent the re-
action and gave the corresponding products 3b–o in
moderate to high yields, although in some cases a longer re-
action time (48 h) is required for the reaction to complete.
It is noteworthy that all halogen substituents (F, Cl, Br, and
I) are tolerated in the reaction conditions, which is advanta-
geous for further transformations (products 3g–j). The re-
sults also shows that steric hindrance has a significant in-
fluence on the reaction since the substrates with substitu-
ent in the 3- or 4-position gave the desired products in
higher yields than their 2-substituted analogues. Fused aryl
ring such as naphthalene and anthracene derivatives 1p–s
could also work well to furnish the corresponding products
3p–s in satisfactory yields.
In order to further explore the scope of our protocol,
aryl iodides were also examined as the coupling partner for
the reaction, and the experimental results are given in Ta-
ble 3. Pleasingly, under the standard conditions, a variety of
aryl iodides could efficiently react with 2a, forming the de-
sired product in good to excellent yields. Both electron-do-
nating groups such as methoxy and methyl, and electron-
withdrawing groups such as trifluoromethyl, nitro, cyano,
fluro, and chloro on the aromatic moiety could be tolerated.
It is noteworthy that 2-iodophenol (4k), whose molecule
contains an active proton, entered into the reaction
smoothly to give the expected product 3u in 61% yield.
We suggested that the cyanation of arylboronic acids
might proceed through an aryl iodide intermediate. To veri-
fy the hypothesis, we investigated the reaction profile of
the copper-mediated cyanation of 1a under the standard
conditions. As can be seen from Figure 2, the iodination
Table 1 Optimization of Copper-Mediated Cyanation of Arylboronic
acid with 2a as Cyanating Agenta
Cu source
oxidant
OH
EtO2C
Ph
B
+
OEt
Ph
CN
solvent
OH
CN
1a
3a
2a
Entry
Cu (equiv)
Oxidant
Solvent
Temp (°C)
Yield (%)b
1
2
CuI (0.2)
CuI (1.0)
–
TBHP
TBHP
TBHP
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DMF
DMF
DMF
100
130
130
130
130
130
130
130
130
130
130
130
130
130
130
29
82 (72)
N.D.c
15
3
4
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuBr (1.0)
CuCl (1.0)
5d
6e
7
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
BQ
trace
trace
N.D.
N.D.
N.D.
N.D.
55
8
9
CuSO4 (1.0)
Cu(OAc)2 (1.0)
CuI (1.0)
10
11
12
13
14
15f
CuI (1.0)
50
CuI (1.0)
28
CuI (1.0)
DTBP
O2
31
CuI (1.0)
10
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Cu source, oxidant
(2 equiv), solvent (2 mL), 24 h, air.
b GC yield with dodecane as internal standard. Number in parentheses is
the yield of isolated product.
c N.D. = not detected.
d Under N2 atmosphere.
e Without 2a.
f Under 1 atm of O2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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C. Qi et al.
Letter
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Table 2 Copper-Mediated Cyanation of Arylboronic Acids with 2a as
Table 3 Copper-Mediated Cyanation of Aryl Iodides with 2a as Cya-
Cyanating Agenta
nating Agenta
CuI, TBHP
EtO2C
CuI, TBHP
EtO2C
Ar
I
OEt
+
Ar B(OH)2
Ar CN
Ar CN
+
OEt
DMF
DMF
CN
CN
4
3
2a
3
2a
1
Entry
4
Yield of 3 (%)b
Entry
1
Yield of 3 (%)b
1
2
4a R = 4-MeO
4b R = 4-F3C
4c R = 4-O2N
4d R = 4-CN
4e R = 4-F
3c 65
3d 73
3e 82
3f 91
3g 81
3h 83
3k 61
3n 91
3o 69
3t 82
3u 61
1
2
1b R = 4-i-Pr
3b 86
3c 47c
3d 90c
3e 70
1c R = 4-OMe
1d R = 4-F3C
1e R = 4-O2N
1f R = 4-NC
1g R = 4-F
3
3
4
4
5
I
5
3f 45
R
6
4f R = 4-Cl
4g R = 3-O2N
4h R = 2-Me
4i R = 2-F
6
3g 68, 95c
3h 85c
3i 70c
3j 68c,d
3k 88
3l 65
7
B(OH)2
7
1h R = 4-Cl
1i R = 4-Br
R
8
8
9
9
1j R = 4-I
10
11
4j R = H
10
11
12
13
14
1k R = 3-O2N
1l R = 2-O2N
1m R = 2-Ph
1n R = 2-Me
1o R = 2-F
4k R = 2-HO
I
3m 60
3n 44
3o 58
12
4l
3q 87
a Reaction conditions: 4 (0.3 mmol), 2a (0.6 mmol), CuI (1 equiv), TBHP (2
equiv), DMF (2 mL), 130 °C, 24 h, air.
B(OH)2
15
16
1p
1q
3p 54
3q 61
b Isolated yield.
B(OH)2
B(OH)2
17
18
1r
1s
3r 52c
3s 69
(HO)2B
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), CuI (1 equiv), TBHP (2
equiv), DMF (2 mL), 130 °C, 24 h, air.
b Isolated yield.
c The reaction was carried out in 48 h.
d 3f was also isolated in 20% yield as a byproduct.
Figure 2 Reaction profile in the copper-mediated cyanation of 1a with
2a as cyanating agent
product, 4-iodobiphenyl, was formed as the major product
at the initial stage of the reaction. The yield of 4-iodobiphe-
nyl reached a maximum value (77% yield) after two hours
and then decreased gradually. At the same time, the cyanat-
ed product 3a was gradually produced after a short period
of induction (0.5 h). Therefore, the iodination products
were proved to be the key reaction intermediates toward
the expected aryl nitriles, and copper(I) iodide acted also as
a supplier of iodide anions in this transformation.
In order to gain more insight into the mechanism of the
reaction, we also attempted to test the existence of cyanide
anions formed in situ during the reaction. As expected,
when the reaction was performed in the absence of 1a un-
der standard reaction conditions, the cyanide anions could
be detected by using a picric acid strip (see Supporting in-
formation for more details).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
C. Qi et al.
Letter
Synlett
Based on the above-mentioned results and previous re-
ports,4b,c,7c we proposed a possible mechanism for the cya-
nation of arylboronic acids (Scheme 2). Initially, the iodina-
tion of arylboronic acid 1 occurred in the presence of CuI
and TBHP, giving rise to aryl iodide 4 as the key intermedi-
ate. Then, the oxidative addition of 4 to Cu(I) took place to
form ArCu(III)I species 5, which could further react with the
cyanide anion generated in situ from the C(sp2)–CN bond
cleavage of 2a to furnish species 6. Finally, the reductive
elimination of 6 would yield the target product 3 and re-
generated the copper catalyst.
(3) (a) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.; Wang, Y. Tetrahedron
Lett. 2014, 55, 1271. (b) Kim, J.; Kim, H. J.; Chang, S. Angew.
Chem. Int. Ed. 2012, 51, 11948.
(4) Recent reports, see: (a) Xu, W.; Xu, Q.; Li, J. Org. Chem. Front.
2015, 2, 231. (b) Zhao, M.; Zhang, W.; Shen, Z. J. Org. Chem.
2015, 80, 8868. (c) Zhu, Y.; Li, L.; Shen, Z. Chem. Eur. J. 2015, 21,
13246. (d) Pan, C.; Jin, H.; Pan, X.; Liu, X.; Cheng, Y.; Zhu, C. J.
Org. Chem. 2013, 78, 9494. (e) Kou, X.; Zhao, M.; Qiao, X.; Zhu,
Y.; Tong, X.; Shen, Z. Chem. Eur. J. 2013, 19, 16880. (f) Zhu, Y.;
Zhao, M.; Lu, W.; Li, L.; Shen, Z. Org. Lett. 2015, 17, 2602.
(5) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem. Int. Ed.
2003, 42, 1661. (b) Cristau, H.-J.; Ouali, A.; Spindler, J.-F.;
Taillefer, M. Chem. Eur. J. 2005, 11, 2483. (c) Schareina, T.; Zapf,
A.; Cotté, A.; Gotta, M. Adv. Synth. Catal. 2011, 353, 777.
(6) Jiang, Z.; Huang, Q.; Chen, S.; Long, L.; Zhou, X. Adv. Synth. Catal.
2012, 354, 589.
(7) (a) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2012, 48,
9933. (b) Wen, Q.; Jin, J.; Mei, Y.; Lu, P.; Wang, Y. Eur. J. Org.
Chem. 2013, 4032. (c) Luo, Y.; Wen, Q.; Wu, Z.; Jin, J.; Lu, P.;
Wang, Y. Tetrahedron 2013, 69, 8400.
(8) (a) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett. 2013, 15, 3354.
(b) Rong, G.; Mao, J.; Zheng, Y.; Yao, R.; Xu, X. Chem. Commun.
2015, 51, 13822.
CuI
Cu(I)
ArB(OH)2
ArCN
ArI
TBHP, air
3
1
4
ArCu(III)CN
ArCu(III)I
6
5
CuI
2a
CN
TBHP, air
(9) (a) Abuhaie, C.-M.; Ghinet, A.; Dubois, J.; Rigo, B.; Bîcu, E. Bioorg.
Med. Chem. Lett. 2013, 23, 5887. (b) Lengyel, L.; Nagy, T. I.; Sipos,
G.; Jones, R.; Dormán, G.; Ürge, L.; Darvas, F. Tetrahedron Lett.
2012, 53, 738. (c) Görmen, M.; Goff, R. L.; Lawson, A. M.; Daïch,
A.; Comesse, S. Tetrahedron Lett. 2013, 54, 2174. (d) El-Gohary,
N. S.; Shaaban, M. I. Eur. J. Med. Chem. 2013, 63, 185. (e) Inouye,
M.; Kim, K.; Kitao, T. J. Am. Chem. Soc. 1992, 114, 778. (f) Scott, J.
S.; deSchoolmeester, J.; Kilgour, E.; Mayers, R. M.; Packer, M. J.;
Hargreaves, D.; Gerhardt, S.; Ogg, D. J.; Rees, A.; Selmi, N.;
Stocker, A.; Swales, J. G.; Whittamore, P. R. O. J. Med. Chem.
2012, 55, 10136.
Scheme 2 Possible reaction mechanism
In summary, we have successfully developed an effi-
cient approach for the synthesis of aryl nitriles via a copper
iodide mediated cyanation of arylboronic acids or aryl io-
dines with ethyl (ethoxymethylene)cyanoacetate as the cy-
anating agent. The reaction involves a C(sp2)–CN bond
cleavage and tolerates a wide range of functional groups, af-
fording the corresponding aryl nitriles in moderate to excel-
lent yields. Further investigation on the reaction mecha-
nism and the synthetic application of the new method are
ongoing in our laboratory.
(10) He, H.; Qi, C.; Hu, X.; Ouyang, L.; Xiong, W.; Jiang, H. J. Org.
Chem. 2015, 80, 4957.
(11) (a) Sawant, D. N.; Wagh, Y. S.; Tambade, P. J.; Bhatte, K. D.;
Bhanage, B. M. Adv. Synth. Catal. 2011, 353, 781. (b) Zhang, L.;
Lu, P.; Wang, Y. Chem. Commun. 2015, 51, 2840. (c) Kim, J.; Choi,
J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012, 134, 2528.
(d) Pawar, A. B.; Chang, S. Chem. Commun. 2014, 50, 448.
(12) Typical Procedure for the Synthesis of Compound 3a
To a 25 mL round-bottom flask was added the mixture of
boronic acid 1a (0.3 mmol), ethyl 2-cyano-3-ethoxyacrylate (2a,
0.6 mmol), CuI (0.3 mmol), t-BuOOH (0.6 mmol) in DMF (2 mL)
successively. The mixture was stirred at 130 °C for 24 h under
air. After the reaction was completed, the mixture was cooled to
room temperature, diluted with H2O (15 mL), and then
extracted with CH2Cl2 (3 × 5 mL). The organic extract was
washed with H2O (3 × 10 mL) and dried over anhydrous Na2SO4.
After removal of the CH2Cl2 in vacuum, the crude product thus
obtained was purified by column chromatography on silica gel
using PE–EtOAc as eluent to give the desired product 3a as a
white solid; yield 72%; mp: 86–87 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.73–7.66 (m, 4 H), 7.59 (d, J = 7.3 Hz, 2 H), 7.51–
7.43 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 145.6, 139.0,
132.5, 129.0, 128.6, 127.6, 127.1, 118.8, 110.8. IR (KBr): 2227,
1605, 1484, 1400, 844, 769, 736, 699, 564, 518 cm–1. MS (EI):
m/z = 179 (100) [M+], 151, 126, 113, 89, 76, 63.
Acknowledgment
We thank the National Natural Science Foundation of China
(21172078 and 21572071) and the Fundamental Research Funds for
the Central Universities (2015zz038) for financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562112.
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References and Notes
(1) Recent reviews on C–CN bond activation, see: (a) Nakao, Y. Top
Curr. Chem. 2014, 346, 33. (b) Tobisu, M.; Chatani, N. Chem. Soc.
Rev. 2008, 37, 300. (c) Chen, F.; Wang, T.; Jiao, N. Chem. Rev.
2014, 114, 8613.
(2) (a) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
(b) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563.
(c) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-
tical Substance: Syntheses, Patents, Applications; Thieme: Stutt-
gart, 2001, 4th ed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D